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Abstract/Summary
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Mutations in the ClC‐7/Ostm1 ion transporter lead to osteopetrosis and lysosomal storage disease. Its lysosomal localization hitherto precluded detailed functional characterization. Using a mutated ClC‐7 that reaches the plasma membrane, we now show that both the aminoterminus and transmembrane span of the Ostm1 β‐subunit are required for ClC‐7 Cl−/H+‐exchange, whereas the Ostm1 transmembrane domain suffices for its ClC‐7‐dependent trafficking to lysosomes. ClC‐7/Ostm1 currents were strongly outwardly rectifying owing to slow gating of ion exchange, which itself displays an intrinsically almost linear voltage dependence. Reversal potentials of tail currents revealed a 2Cl−/1H+‐exchange stoichiometry. Several disease‐causing CLCN7 mutations accelerated gating. Such mutations cluster to the second cytosolic cystathionine‐β‐synthase domain and potential contact sites at the transmembrane segment. Our work suggests that gating underlies the rectification of all endosomal/lysosomal CLCs and extends the concept of voltage gating beyond channels to ion exchangers.
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